Composition for inhibiting increase of blood sugar level or lowering blood sugar level

ABSTRACT

A composition for inhibiting an increase in, or lowering, a blood sugar level, which comprises, as a main component, a concentrate of a hot water or alcohol extract of leaves of  Lagerstroemia speciosa , Linn. or Pers. and has an corosolic acid content of 0.01 to 15 mg per 100 mg of the concentrate, and a method of inhibiting an increase in, or lowering, a blood sugar level by oral administration of the composition.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 09/437,342filed on Nov. 10, 1999, now U.S. Pat. No. 6,485,760, which claimspriority from Japanese Patent Application JP 10-349667 filed on Dec. 9,1998.

DETAILED DESCRIPTION OF THE INVENTION

1. Field of the Invention

The present invention relates to a composition for inhibiting anincrease of a blood sugar level or lowering a blood sugar level. Morespecifically, it relates to a composition for inhibiting an increase ofa blood sugar level or lowering a blood sugar level, which compositioncontains extract components from Lagerstroemia Speciosa, Linn. or Pers.as a main component and has a specific content of corosolic acid.

2. Prior Art of the Invention

Lagerstroemia Speciosa, Linn. or Pers. comes under the loosestrifefamily of Myrtales and is generally called “queen's crape myrtle” aswell, and it occurs widely in south east Asian areas including thePhilippines, India, Malaysia, southern China and Australia. In thePhilippines in particular, dry leaves and flowers of LagerstroemiaSpeciosa, Linn. or Pers. are decoted and taken as a drink. This drink isalso well known as a folk medicine against diabetes.

Leaves of Lagerstroemia Speciosa, Linn. or Pers. have received attentionand an extract thereof has been analyzed for obtaining some components.It has been accordingly reported that corosolic acid is contained as oneof the components and that the corosolic acid has been studied for itsactivity by using Ehrlich Ascites Tumour Cells to show that it is asubstance which activates the mobility of grape sugar [Chem. Pharm.Bull. 41(12) 2129-2131 (1993)].

The above report is concerned with results of in vitro experiments andmerely suggests results of first-stage discrimination test ofanti-diabetes activities of corosolic acid.

JP-A-5-310587 discloses an anti-diabetes preparation containing, as aningredient, a concentrated dry substance (Lagerstroemia Speciosa, Linn.or Pres. powder extract) obtained by extracting leaves of LagerstroemiaSpeciosa, Linn. or Pers. in hot water or an organic solvent. The abovepreparation is an easily prepared and high-safety anti-diabetespreparation produced by taking out a water-soluble fraction and alipid-soluble fraction from an extract of leaves of LagerstroemiaSpeciosa, Linn. or Pers. and adjusting it to a dry extract. The abovepublication discloses a preferred embodiment in which the powder extractis diluted, e.g., in a concentration of 2% and taken as a drink, and theanti-diabetes activity thereof is confirmed by an animal experimentusing mice diseased with diabetes.

As already described, dry leaves of Lagerstroemia Speciosa, Linn. orPers. have been used as having an effect on the therapy of diabetes infolk medicine. However, it is not clearly known what component(s) of theleaves of Lagerstroemia Speciosa, Linn. or Pers. has/have humananti-diabetes activity. It is known that corosolic acid is contained asone component, while the activity thereof is a mere result of a study ofthe function to activate the mobility of grape sugar in an in vitroexperiment using cells.

Further, there has been no specific clinical knowledge of component(s)of the extract of leaves of Lagerstroemia Speciosa, Linn. or Pers. whichhas/have activity in the therapy of human diabetes. Moreover, there hasbeen found no knowledge obtained by studying a relationship betweencomponent(s) of the extract of leaves of Lagerstroemia Speciosa, Linn.or Pers. and an increase in a human blood sugar level.

The present inventor has therefore studied a relationship betweencomponent(s) of an extract of leaves of Lagerstroemia Speciosa, Linn. orPers. and an increase or inhibition of an increase in human blood sugarlevel on the basis of clinical tests. When a composition which was aconcentrated extract of leaves of Lagerstroemia Speciosa, Linn. or Pers.and which had a specific content of corosolic acid was administered tomild-case diabetes patients who had a fasting blood sugar level ofslightly higher than approximately 110 mg/dl and who wereinsulin-non-dependent, it was found that an increase in blood sugarlevel was inhibited and that the blood sugar levels decreased onaverage.

According to studies by the present inventors, it has been also foundthat the composition which had a specific content of corosolic acid canbe obtained by extracting, concentration and drying leaves ofLagerstroemia Speciosa, Linn. or Pers., under a specific condition.

MEANS TO SOLVE THE PROBLEMS

According to the present invention, therefore, there is provided acomposition for inhibiting an increase blood sugar level, whichcomprises, as a main component, a concentrate of a hot water or alcoholextract of leaves of Lagerstroemia Speciosa, Linn. or Pres. and has acorosolic acid content of 0.01 to 15 mg per 100 mg of the concentrate.

According to the present invention, further, there is provided a methodof inhibiting an increase in a blood sugar level, which comprises orallyadministering the above composition to a patient who is expected tosuffer an increase in blood sugar level from a normal blood sugar level.

Further, according to the present invention, there is provided a methodof lowering a blood sugar level to a normal level, which comprisesorally administering the above composition to a mild-case diabetespatient having a blood sugar level higher than a normal level to someextent or a serious diabetes patient having a high blood sugar level.

The present invention will be explained more specifically hereinafter.

Corosolic acid is one of triterpenoids having the following structuralformula.

It is considered that the activity of the composition of the presentinvention in inhibiting an increase in, or lowering, a human blood sugarlevel is caused by the interaction of a specific content of corosolicacid in the concentrate and extracted components of leaves ofLagerstroemia Speciosa, Linn. or Pers.

Leaves of Lagerstroemia Speciosa, Linn. or Pers. used as a raw materialfor the composition of the present invention refer to green leaves ofLagerstroemia Speciosa, Linn. or Pers. which occurs in the Philippinesor some other areas or a dry product prepared by drying the same. Thegreen leaves may be dried by leaving it in atmosphere, by air-drying orby forcible drying. Preferably, the drying is carried out by so-calledtoasted-drying until the leaves have a water content of 20% by weight orless, preferably 10% by weight or less, for preventing the growth ofmicroorganisms and attaining storage stability.

Green leaves of Lagerstroemia Speciosa, Linn. or Pers. may be extractedas they are, while it is desirable to pulverize the dry leaves or cutthem into pieces before the extraction.

The method and condition of extracting leaves of Lagerstroemia Speciosa,Linn. or Pers. in hot water or an alcohol and concentrating the extractare not specially limited, while there should be employed a method and acondition under which a resultant concentrate has a specific content ofcorosolic acid. That is, the concentrate preferably has a corosolic acidcontent of 0.01 to 15 mg per 100 mg of the concentrate (dry solidsubstance). The corosolic acid content per 100 mg of the concentrate ispreferably 0.1 to 15 mg, more preferably 0.2 to 12 mg, particularlypreferably 0.5 to 10 mg.

In the composition of the present invention, those components of theleaves of Lagerstroemia Speciosa, Linn. or Pers. which are other thancorosolic acid also have an effect on the activity, and it is requiredto take account of components to be extracted and a concentrating methodand condition with regard to other components. A preferred embodiment ofa proper method and a proper condition will be apparent from anexplanation to be given later.

Method 1

In this method, a pulverization product of dry leaves of LagerstroemiaSpeciosa, Linn. or Pers. (raw material) added to ethanol or an ethanolaqueous solution (ethanol content 50 to 80% by weight) in an amount 5 to20 times, preferably 8 to 10 times the weight of the raw material, andthe mixture is refluxed under heat at a temperature between roomtemperature and 90° C., preferably approximately between 50° C. and 80°C., for 30 minutes to 2 hours. The above extraction is repeated twice orthree times. The resultant extract may be decolorized as required byadding 5 to 10% by weight, based on the raw material, of activatedcarbon. The decolorization is useful for expanding the use range of thecomposition of the present invention to foods, and the like. Then, theextract is filtered and concentrated at a temperature of 60° C. or lowerunder reduced pressure to obtain a solid, and the solid is dried at atemperature between 50° C. and 70° C. under reduced pressure (higherreduction rate than that during the concentration). The thus-obtainedsolid is pulverized to obtain a powdery concentrate. The concentrateobtained by the above method has a specific content of corosolic acidand contains an effective amount of other components as well.

Method 2

This method is an extraction method using methanol or a methanol aqueoussolution. In this method, the extraction is carried out in methanol or amethanol aqueous solution (methanol content 50 to 90% by weight) in anamount 3 to 20 times the weight of the raw material. The extractionprocedure is preferably carried out at a temperature between roomtemperature and 65° C. for 30 minutes to 2 hours. The number of times ofthe extraction procedure is not limited to once, and the extractionprocedure may be carried out twice or more. The obtained extract isdecolorized as required, and concentrated under the same conditions asthose in the above method 1, whereby a solid can be obtained.

Method 3

This method 3 is an extraction method using hot water. There is used hotwater in an amount 3 to 20 times the weight of the raw material, and theextraction is carried out at a temperature between 50° C. and 90° C.,preferably between 60° C. and 85° C., for 30 minutes to 2 hours.Desirably, the concentration and drying after the extraction are carriedout for a relatively short period of time since active components may besometimes deteriorated when the concentrate is maintained at a hightemperature for a long period of time. For this reason, it isadvantageous to carry out the concentration and the drying under reducedpressure.

The above-explained methods 1 to 3 have been described for explainingbasic methods and conditions, and these methods may be altered and/orcombined as required. For example, the method 1 and the method 2 may becombined. Of the above methods 1 to 3, the methods 1 and 2 arepreferred, and the method 1 is particularly preferred.

Function and Effect of the Composition of the Present Invention

When used as a preparation for inhibiting an increase in, or lowering,the blood sugar level, the composition of the present invention has thefollowing advantages.

(a) It has been reported that conventional oral preparations for thetherapy of diabetes such as a sulfonyl urea preparation, a biguanidepreparation, an insulin resistant amelioration preparation, etc., causesside effects such as hepatopathy, disorder of digestive organs, nausea,vomitting, etc., while the composition of the present invention is freeof these side effects.

(b) The above conventional preparations for the therapy of diabetes endtheir effects when the administration thereof is discontinued, while thecomposition of the present invention continues to have an effect and hasa continuing effect like traditional Chinese medicine since the bloodsugar level does not increase when its administration is discontinued.

(c) The composition of the present invention does not cause a decreasein the blood sugar level when people having a normal blood sugar leveltakes it.

(d) It is considered that the above advantages of the composition of thepresent invention are exhibited since corosolic acid contained in leavesof Lagerstroemia Speciosa, Linn. or Pers. activates grape sugartransportation even if its concentration is very low.

It is considered that intensification of the grape sugar transportationactivity of corosolic acid in “intaking of sugar” and “conversion ofsugar to energy” is a function different from that of conventionalpreparations for the therapy of diabetes.

(e) It is also assumed that the composition of the present invention hasanother activity in inhibiting the digestion and absorption of glucideby preventing the function of typical digestive enzyme of glucide. It isconsidered that the above activity is caused by the interaction ofcorosolic acid and other component(s) in the concentrated extract ofleaves of Lagerstroemia Speciosa, Linn. or Pers.

The composition of the present invention can therefore inhibit anincrease in a blood sugar level by orally administering it to patientswho are expected to suffer an increase in blood sugar level from anormal blood sugar level. The above oral administration can be continuedfor a long period of time, and even if the composition of the presentinvention is continuedly taken for a long period of time, the bloodsugar level comes to be lower than a normal blood sugar level in nocase. Further, the oral administration causes no or almost no otherharms or side effects.

Further, when orally administered to diabetes patients, the compositionof the present invention can lower their blood sugar level to a normallevel. The composition of the present invention can work on any one ofmild-case patients having a blood sugar level higher than a normal bloodsugar level to some extent and serious patients having a considerablyhigher blood sugar level.

When the composition of the present invention is orally administered,desirably, the dosage of the concentrate having a corosolic acid contentof 0.01 to 15 mg per kg of a human body weight per day is 50 mg to 1,000mg, preferably 70 mg to 800 mg. Specifically, the oral administration ispreferably separated to twice or three times a day. Desirably, further,the oral administration of the composition of the present invention isconducted continuedly for at least one month, preferably for at leastthree months.

The composition of the present invention may have the prepartion form ofa powder or granules, and it may also have the preparation form of atablet such as pellets or an encapsulated preparation.

EXAMPLES

The present invention will be explained more specifically with referenceto Examples hereinafter.

Example 1

(1) Preparation of concentrate from dry leaves of LagerstroemiaSpeciosa, Linn. or Pers.

1 Kg of dry leaves of Lagerstroemia Speciosa, Linn. or Pers. from thePhilippines were cut, placed in 5 liters of a 80 wt % ethanol aqueoussolution and extracted under reflux under heat (approximately 85° C.)for 1.5 hours. After the extraction, the leaves of LagerstroemiaSpeciosa, Linn. or Pers. were separated by filtration, again placed a 80wt % ethanol aqueous solution and extracted under reflux under heat(approximately 85° C.) for 1.5 hours. The leaves of LagerstroemiaSpeciosa, Linn. or Pers. were separated by filtration. Extracts obtainedby the first and second extraction procedures were combined, and 500 gof activated carbon was added to carry out decolorization. After theactivated carbon was removed, ethanol and water were removed underreduced pressure at 60° C. to give a concentrate. Then, the concentratewas maintained further under reduced pressure at 60° C. to give a drysolid. The solid was pulverized to give 150 g of a powdery concentrate.

(2) Analysis of corosolic acid

One gram of the powder concentrate obtained in the above (1) wasdissolved in 10 ml of methanol and analyzed by high-performance liquidchromatography (HPLC) to show a corosolic acid content of 30 mg in theabove concentrate (corresponding to 3 mg of corosolic acid per 100 mg ofthe concentrate).

(3) Preparation of tablet

The powdery concentrate obtained in the above (1) was used to preparetablets containing the following components for a clinical test.

Components % by weight Powdery concentrate 50 Dietary fiber^(*1) 20Sucrose fatty acid ester 3 Lactose 22 Hardened oil^(*2) 5 100^(*1)Crystalline cellulose ^(*2)Hardened rapeseed oil

The above components were homogeneously mixed and prepared into tabletshaving a weight of 250 mg each (“tablets A” hereinafter) with a tabletmachine.

Further, tablets containing no powdery concentrate (“tablets B”hereinafter) which were indistinguishable from the tablets A wereprepared in the same manner as above except that diluents alone wereused without the powdery concentrate.

(4) Clinical test

Twenty-two mild-case insulin non-dependent patients having a a fastingblood sugar level of approximately 100 to 210 mg/dl were classified intotwo groups.

The Group I (11 patients of one group) were allowed to take threetablets A each time after meals three times a day with a cup of waterfor 4 weeks from the beginning of the first to the end of the fourthweek, and the tablets B were administered under the same conditions for4 weeks from the beginning of the fifth week.

On the other hand, the Group II (11 patients of the other group) wereallowed to take three tablets B each time after meals three times a daywith a cup of water for 4 weeks from the beginning of the first to theend of the fourth week, and the tablets A were administered under thesame conditions for 4 weeks from the beginning of the fifth week.

In the beginning of the administration, after 4 weeks and after 8 weeksfrom the administration, bloods of the patients were sampled three timesand studied for blood sugar levels. Table 1 shows the results.

TABLE 1 After After Beginning 4 weeks 8 weeks Group I 169.1 → 132.8 →143.4 (11 patients) tablet A tablet B Average (mg/dl) Group II 129 → 128→ 110 (11 patients) tablet B tablet A Average (mg/dl)

The tablets A were studied for a significant difference to show aProb>(T) value of 0.0030 and that the tablets A had a high-degreesignificant difference in decreasing the blood sugar level.

What is claimed is:
 1. A composition for inhibiting an increase in, orlowering, a blood sugar level, in a human patient in need thereof,consisting essentially of: a concentrate of ethanol or ethanol aqueoussolution extract of leaves of Lagerstroemia Speciosa, Linn. or Pers.having a corosolic acid content of 0.01 to 15 mg per 100 mg of theconcentrate.
 2. The composition according to claim 1, wherein saidethanol solution contains 50 to 80 by weight of ethanol.